ZNF259 promotes breast cancer cells invasion and migration via ERK/GSK3β/snail signaling

Abstract

PurposeZinc finger protein 259 (ZNF259), also known as ZPR1, is a zinc finger-containing protein that can bind the intracellular tyrosine kinase domain of EGFR. At present, our knowledge on ZNF259 in cancers is limited. Here, we aimed to explore the biological functions of ZNF259 in breast cancer and reveal their mechanisms.Patients and methodsThe expression of ZNF259 was measured in 133 cases of breast cancer by immunohistochemistry. The online database Kaplan–Meier (KM) Plotter Online Tool was used to analyze the relationship between ZNF259 expression and breast cancer patient survival prognosis. Plasmid transfection and small interfering RNA and inhibitor treatments were carried out to explore the functions of ZNF259 in breast cancer cell lines and its potential mechanism. Matrigel invasion and wound healing assays were performed to detect the invasion and migration ability of cancer cells. In addition, protein expressions in tissues and cells were determined by Western blotting.ResultsZNF259 expression was much higher in breast cancer cells than in the adjacent normal breast duct glandular epithelial cells (75.94% vs 7.52%, P<0.001) and was closely related to the breast cancer patients’ TNM stages (P=0.013) and lymph node metastasis (P=0.021). Knockdown of ZNF259 could downregulate p-ERK, p-GSK3β, and Snail expression, and upregulate the expression of E-cadherin and ZO-1, and then it also inhibited invasion and migration by the breast cancer cell lines MCF-7 and MDA-MB-231. Correspondingly, ZNF259 transfection could upregulate p-ERK, p-GSK3β, and Snail expression, and downregulate E-cadherin and ZO-1 expression, which led to stronger invasion and migration abilities of cancer cells. Furthermore, the ERK inhibitor U0126 could reverse all these effects induced by ZNF259 transfection.ConclusionZNF259 could promote breast cancer cell invasion and migration by activating the ERK/GSK3β/Snail signaling pathway.

Extracellular-Signal Regulated Kinase: A Central Molecule Driving Epithelial–Mesenchymal Transition in Cancer

“…The ERK pathway comprises several proteins that belongs to the family of mitogen-activated protein kinases (MAPK). These regulate diverse physiological and cellular processes, such as gene expression, cell division, survival, apoptosis, differentiation, and motility [15,16]. In metastatic processes, the MAPKs regulate EMT, invasion, angiogenesis, and resistance to therapy [7].…”

“…This leads to an increase in the expression of ZO-1, claudin, and occludin and adequate formation of adherent junctions [177]. Likewise, the expression of ZNF259 (Zinc finger protein 259) in MCF-7 and MDA-MB-231 cell lines increases the phosphorylation of MEK, ERK, and GSK3β and expression of Snail, while diminishing the ERK-dependent expression of EMT markers [16]. On the other hand, in the T47D and MDA-MB-231 cell lines, a positive feedback was observed between the EMT transcription factor Snail and p-ERK, which favors the expression and nuclear localization of both proteins [178].…”

<p>C14orf159 suppresses gastric cancer cells&rsquo; invasion and proliferation by inactivating ERK signaling</p>

“…A previous study showed that ERK inhibitor U0126 could inhibit the levels of p-ERK and Snail and then restore E-cadherin expression. Correspondingly, the increased cell invasion and migration were also reversed by U0126 16. Moreover, elevated E-cadherin significantly suppressed the cell proliferation and migration and E-cadherin was inhibited by activating ERK/Snail signaling 17.…”

Identification of triptonide as a therapeutic agent for triple negative breast cancer treatment

“…Because AKT and ERK are well-established activators of SNAI1 expression in cancer cells 15 , 16 , we tested whether they regulate the drastic elevation of SNAI1 levels in TN-resistant TNBC cells. To do so, we compared activated AKT and ERK levels in TN-resistant and parental cells using immunoblotting.…”